Riener Marc-Oliver, Nikolopoulos Elisabeth, Herr Alexander, Wild Peter Johannes, Hausmann Michael, Wiech Thorsten, Orlowska-Volk Marzenna, Lassmann Silke, Walch Axel, Werner Martin
Institute of Pathology, University Hospital Freiburg, Freiburg i. Br., Germany.
Hum Pathol. 2008 Nov;39(11):1621-9. doi: 10.1016/j.humpath.2008.02.021. Epub 2008 Jul 24.
Tubular breast carcinoma is a highly differentiated carcinoma with an excellent prognosis. Distinct genetic alterations in tubular breast carcinoma cells have been described, especially broad genetic losses on the q-arm of chromosome 16. These are more common in lobular breast carcinoma and low-grade ductal carcinoma in situ than in ductal breast carcinoma and high-grade ductal carcinoma in situ. To further delineate the molecular changes involved in tubular breast carcinoma more precisely, we examined 23 formalin-fixed and paraffin wax-embedded tissue samples (21 of tubular breast carcinoma and 2 of nonneoplastic breast epithelium) by microarray-based comparative genomic hybridization focusing on 287 genomic target clones of oncogenes and tumor suppressor genes. The results obtained from all nonneoplastic tissue samples of breast epithelium indicate no DNA copy number changes. In the tubular breast carcinoma samples, the highest frequencies for DNA sequence copy number losses were detected for CDH13 (in 86% of the samples) and MSH2, KCNK12 (in 52% of the samples). The highest frequencies of DNA sequence copy number gains were detected for HRAS and D13S319XYZ (each in 62% of the samples). Using principal component analysis, 3 subgroups of tubular breast carcinomas showing relative genetic changes were identified. For validation, the most frequent DNA copy number loss for CDH13 (18/21) was confirmed using fluorescence in situ hybridization in 4 of 5 tubular breast carcinomas analyzed. The newly identified genes with considerable copy number changes may include so far unknown candidate genes for the development and progression of tubular breast carcinoma, such as CDH13. The study provides the starting point for further delineating their detailed influence on the pathogenesis of tubular breast carcinoma.
管状乳腺癌是一种高分化癌，预后良好。已有文献报道了管状乳腺癌细胞中存在明显的基因改变，尤其是16号染色体长臂上广泛的基因缺失。这些改变在小叶乳腺癌和低级别导管原位癌中比在导管乳腺癌和高级别导管原位癌中更常见。为了更精确地进一步描绘管状乳腺癌所涉及的分子变化，我们通过基于微阵列的比较基因组杂交技术，聚焦于287个癌基因和肿瘤抑制基因的基因组靶标克隆，检测了23个福尔马林固定石蜡包埋组织样本（21个管状乳腺癌样本和2个非肿瘤性乳腺上皮样本）。从所有乳腺上皮非肿瘤组织样本中获得的结果表明没有DNA拷贝数变化。在管状乳腺癌样本中，检测到CDH13（86%的样本）、MSH2、KCNK12（52%的样本）的DNA序列拷贝数缺失频率最高。检测到HRAS和D13S319XYZ（各62%的样本）的DNA序列拷贝数增加频率最高。使用主成分分析，识别出了显示相对基因变化的3个管状乳腺癌亚组。为进行验证，在分析的5个管状乳腺癌中的4个中，使用荧光原位杂交技术确认了CDH13最常见的DNA拷贝数缺失（18/21）。新发现的具有相当拷贝数变化的基因可能包括迄今为止未知的管状乳腺癌发生和发展的候选基因，如CDH13。该研究为进一步描绘它们对管状乳腺癌发病机制的详细影响提供了起点。
